1. Field of the Invention
The present invention relates to a series of chemical compounds which were found to have an activity for inducing the production and secretion of nerve growth factor (hereinafter abbreviated as NGF) in the local tissues of brain. The invention also relates to medicinal compositions containing these chemical compounds as effective ingredients.
The chemical compounds of this invention inhibit the progress of dysfunction of responsible nerves projecting into said local tissues by the activity of these compounds.
The chemical compounds further accelerate the repair of partly degenerated nerves and/or the reinnervation by intact neurons. The medicinal compositions of this invention containing aforesaid chemical compounds exert preventive and therapeutic effects on regressive disorders in the central nervous system including Senile Dementia of Alzheimer type (hereinafter abbreviated as SDAT) according to the action mechanism depending upon the above-mentioned "brain plasticity".
2. Description of the Prior Art
Basic and clinical researches have been promoted in order to establish early diagnosis and etiological therapy for various old age diseases with the advancement on average span of life in the world. The regressive disorders in the central nervous system is also one of the principal research subjects. SDAT, a typical disease in particular, is becomming an object of serious social concern as a result of a remarkable increase especially in advanced countries and a progressive and tragic course of the disease.
Particularly in recent years, many researchers and clinicians have investigated extensively and yet neither fundamental elucidation of the disease nor effective early diagnosis and therapy have been established. Many pathological findings, however, have been accumulated on the direct cause of failure in immediate memory and disorientation which are characteristic early symptoms of SDAT. According to these findings, the cause is a progressive degeneration in magnocellular cholinergic tracts projecting from basal forebrain into cerebral cortex and hiprocampus which are the centers of memory and learning, and an accompanied dysfunction in said responsible region. In addition, precursors in acetylcholine biosymthesis or inhibitors of choline esterase were actually administered to SDAT patients as an activation treatment for brain cholinergic neuron. Cases of partial improvement have been reported whereas generally no or only transient effect has been found as expected.
NGF has been the subjects of many researches since its discovery by R. Levi-Montalcini and S. Cohen et al. It has already been proved by several experiments in physiological chemistry that NGF is an essential factor for the peripheral nervous system relating to the differentiation and growth of sensory and sympathetic nerves in fetus and further to the survival and maintenance of functions in the sympathetic neurons of adult.
NGF, however, is a patent biologically active substance in an ultra trace amount. In spite of the long term researches, precise information have not been obtained on the tissue distribution and movement which directly prove vital functions. Most recently, development and improvement have been advanced on highly sensitive enzyme linked immunosorbent assay (hereinafter abbreviated as ELISA) on the active subunit of NGF, e.g. .beta.-NGF (hereinafter simply referred to as NGF). Thus satisfactory sensitivity and specificity for the above examination have been attained [S. Furukawa et al, J. Neurochem., 40, 734-744 (1983); S. Korshing and H. Thoenen, Proc. Natl. Acad. Sci. USA, 80, 3513-3516 (1983)].
Besides NGF gene was cloned and sequenced. A method for the determination of messenger RNA (hereinafter abbreviated as m RNA) for .beta.-NGF has been established by using its complemental DNA (hereinafter abbreviated as cDNA) as a probe [D. L. Shelton and L. F. Reichardt, Proc. Natl. Acad. Sci. USA, 81, 7951-7955 (1984); R. Heumann et al., EMBO J., 3, 3183-3189 (1984)].
By applying these procedures, a clear positive correlation has been proved between the sympathetic innervation in the peripheral nervous system and gene expression of NGF.
More surprisingly, NGF has also been detected in the central nervous system of rats, particularly in hippocampus, neocortex, and basal forebrain, e.g.,septum, olfactory bulb, diagonal band of Broca, and nucleus basalis magnocellularis. In addition, its mRNA content has been found at a high level in hippocampus and neocortex. On the other hand, the content in the septum of basal forebrain has been found at the same level as in other regions of brain where no NGF antigen was detected [S. Korshing et al., EMBO J., 4, 1389-1393 (1985)]. Thereafter the results have been successively traced by other research groups [D. L. Shelton and L. F. Reichardt, Proc. Natl. Acad. Sci. USA, 83, 2714-2718 (1986); S. R. Whittemore et al., Proc. Natl. Acad. Sci. USA, 83, 817-821 (1986)].
According to the aforesaid results, NGF gene is expressed not only in the peripheral nervous system, but in the central nervous system. Furthermore it was proved that NGF is produced and secreted in the neocortex and hippocampus, the centers of memory and learning, where the cholinergic tracts project from their origins in the base forebrain and then uptaken at the nerve endings and transported in the retrograde manner through axons to reach somata in origins. NGF has already been proved by a series of physiological experiments that it is an essential factor for the survival and maintenance of functions to the cholinergic tracts. Therefore, the result has demonstrated the assumption that NGF has a specific function as a "neurotropic factor" also in the central nervous system. Thereafter the experiment has been traced by several research groups and has also been proved by the investigation of NGF receptors and their distribution in brain.
The present inventors have investigated the function of NGF as the neurotropic factor in the central nervous system. As afore-mentioned in the prior art, the disorder in memory and learning which are the early symptoms of SDAT is directly caused by progressive degeneration of cholinergic tracts and consequent dysfunction of brain domains under their control.
The inventors, however, now stand on the point of view that the failure of production and secretion of NGF in particular regions of brain can be the truly fundamental cause of early symptoms in SDAT.
That is, conventional symptomatic trials against SDAT such as supplement and/or availability improvement therapies of acetylcholine have been made without any remarkable result. On the other hand, it is believed to be much effective if a functionally vicious cycle between responsible nerves and regions under its control could be broken by maintaining the production and secretion of NGF in cerebral cortex and hippocampus.
Besides the process for the preparation of human-type .beta.-NGF in a large amount has already been developed by the gene-manipulation. Many pharmacological and pharmaceutical limitations, however, still exist on the supplemental therapy of NGF itself which is a protein having a molecular weight of above 10,000. Regarding the application for the central nervous system in particular, the prospect for its development has not yet been furnished.